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Method for synthesizing and purifying 5-isosorbide mononitrate

A technology of isosorbide dinitrate and purification method, which is applied in the direction of organic chemistry, can solve the problems of incomplete selective reduction, high catalyst cost, and difficulty in purification, and achieve the effects of easy removal of impurities, low price, and short reaction cycle

Active Publication Date: 2014-03-19
QINGDAO HUANGHAI PHARM CO LTD
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  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this route is that the selective reduction is not complete, and there will still be 2-isosorbide mononitrate and isosorbide dinitrate mixed in the product, which brings difficulties to the purification
At the same time, the cost of selective reducing agent and catalyst is high, resulting in high cost

Method used

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  • Method for synthesizing and purifying 5-isosorbide mononitrate
  • Method for synthesizing and purifying 5-isosorbide mononitrate
  • Method for synthesizing and purifying 5-isosorbide mononitrate

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Embodiment 5

[0032] The synthesis and purification method of present embodiment 5-isosorbide mononitrate are as follows:

[0033] 1. In a 100 mL dry three-necked flask, add acetic acid (3.6 g, 60 mmol) and acetic anhydride (6.12 g, 60 mmol), keep the internal temperature of the reaction at 0±1 °C, and start adding concentrated nitric acid (5.82 g , 60 mmol), and the dropping time was 30 min to prepare a nitrating reagent (concentrated nitric acid was activated by acetic acid and acetic anhydride). After the dropwise addition, keep the reaction at 0±1°C for 30 min.

[0034] Slowly add the prepared nitrating reagent dropwise into a 250 mL single-necked bottle containing isosorbide (8.76 g, 60 mmol), 10 mL of acetic acid and 5 mL of acetic anhydride (activated concentrated nitric acid and isosorbide in the nitrating reagent The reaction occurs, the acetic acid and acetic anhydride added here are used as solvents), the reaction temperature is kept at 12±2 °C, and the dropwise addition time is...

Embodiment 2

[0039] The synthesis and purification method of present embodiment 5-isosorbide mononitrate are as follows:

[0040] 1. Add acetic acid (3.6 g, 60 mmol) and acetic anhydride (6.12 g, 60 mmol) into a 100 mL dry three-necked flask, keep the internal temperature of the reaction at -5±1 °C, and start adding concentrated nitric acid (6.98 g, 72 mmol), the dropping time was 30 min. After the dropwise addition, keep at -5±1°C for 45 min.

[0041] Slowly add the prepared nitration reagent dropwise into a 250 mL single-necked bottle filled with isosorbide (8.76 g, 60 mmol), 10 mL of acetic acid and 5 mL of acetic anhydride, keeping the reaction temperature at 15±2 °C, and the dropping time for 1 h. After the dropwise addition, keep the temperature at 15±2°C for 2 h.

[0042] 2. Add 100 mL of water to the reaction solution to quench the reaction. The reaction solution was left to stand at 0 °C for 3 h to crystallize, and a white solid precipitated out. It was filtered while cold, an...

Embodiment 3

[0046] The synthesis and purification method of present embodiment 5-isosorbide mononitrate are as follows:

[0047] 1. In a 100 mL dry three-necked flask, add acetic acid (3.6 g, 60 mmol) and acetic anhydride (6.12 g, 60 mmol), keep the internal temperature of the reaction at 0±1 °C, and start adding concentrated nitric acid (6.98 g , 72 mmol), the dropping time was 30 min. After the dropwise addition, keep the reaction at 0±1°C for 30 min.

[0048] Slowly add the prepared nitration reagent dropwise into a 250 mL single-necked bottle filled with isosorbide (8.76 g, 60 mmol), 10 mL of acetic acid and 5 mL of acetic anhydride, keeping the reaction temperature at 12±2 °C, and the time for dropping for 1 h. After the dropwise addition, keep the temperature at 12±2°C for 2 h.

[0049] 2. Add 100 mL of water to the reaction solution to quench the reaction. The reaction solution was left to stand at 0 °C for 3 h to crystallize, and a white solid precipitated out. It was filtered...

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Abstract

The invention provides a method for synthesizing and purifying 5-isosorbide mononitrate. The method comprises the steps of: (1) preparing a nitrifying reagent from concentrated nitric acid, acetic acid and acetic anhydride, and directly nitrifying isosorbide to obtain an isosorbide nitride mixture; (2) adding water to arouse a quenching reaction, separating out 2,5-isoscrbide dinifrate at a temperature ranging from 0 to 5 DEG C, and filtering out the 2,5-isoscrbide dinifrate; (3) reacting the filtrate with sodium hydroxide to prepare an isosorbide mononitrate sodium salt aquo-complex, filtering, and hydrolyzing the sodium salt; and (4) extracting, concentrating and recrystallizing to obtain high-purity 5-isosorbide mononitrate. The preparation method provided by the invention is simple, safe, easy to operate and short in reaction period; impurities are easy to remove, and the yield and the purity are high; therefore, the method lays a foundation for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis and purification, in particular to a synthesis and purification method of isosorbide 5-mononitrate. Background technique [0002] 5-isosorbide mononitrate, chemical name 1,4,3,6-dianhydro-D-sorbitol-5-mononitrate, also known as isosorbide dinitrate, is the main biological activity of isosorbide dinitrate in the body The metabolite, through the release of nitric oxide, activates guanylate cyclase, which relaxes vascular smooth muscle and dilates peripheral arteries and especially veins. Isosorbide 5-mononitrate is suitable for the long-term treatment of coronary heart disease, the prevention of angina pectoris, and the treatment of persistent angina pectoris after myocardial infarction. [0003] Due to the complex process and purification steps of synthesizing isosorbide 5-mononitrate and the low yield, the cost is high and the industrial production is limited. At present, there are th...

Claims

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Application Information

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IPC IPC(8): C07D493/04
CPCC07D493/04
Inventor 王世潇高永吉胡杰李延顺黄清华
Owner QINGDAO HUANGHAI PHARM CO LTD
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